DEVELOPMENTAL ORIGINS OF DIABETES AND CARDIOVASCULAR DISEASE. Goals

Transcription

1 DEVELOPMENTAL ORIGINS OF DIABETES AND CARDIOVASCULAR DISEASE Goals Evolutionary paradox of obesity/diabetes Thrifty gene hypothesis Thrifty phenotype hypothesis Effects of small for gestational age (SGA) Adaptive role of visceral fat in SGA infants Fixed demands of brain development Role of infection 1

2 Obesity Trends* Among U.S. Adults BMI > 30 United States (*BMI 30, or about 30 lbs. overweight for 5 4 person) BRFSS, CDC No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% All-cause mortality by waist circumference in the Cancer Prevention Study II Nutrition Cohort, Jacobs, E. J. et al. Arch Intern Med 2010;170: Copyright restrictions may apply." 2

3 Inflammation Cani et al Curr Pharm Design 15, Holloszy. J Appl Physiol Feb;82(2):

4 Fontana et al Proc Natl Acad Sci U S A Apr 27;101(17): Calorie Restriction Total testosterone Low thyroid hormone Lower bone density Muscle loss Cangemi, et al. Aging Cell Apr;9(2): Epub 2010 Jan 20. 4

5 The median life span and fecundity of higher eukaryotes are negatively affected by a very low food intake L. Fontana et al., Science : Abdominal Fat 5

6 Diabetes Insulin resistance Decreased glucose uptake Hyperglycemia What explains the detrimental effects of belly fat? 6

7 Thrifty Genotype One of the earliest evolutionary medicine hypotheses Remember our discussion of Pima Indians? Some populations have astronomical rates of diabetes. (Neel, 1962) Imagine an island population Two kinds of people on the island ú Some are large and lean, little energy storage, more growth. ú Others are smaller and with more adipose reserves, and less energy used for growth and maintenance. 7

8 Island Famine Genes that store fat and conserve energy. Survive famine better, leaving more descendants Unpredictable environment selects for thrifty genes Explains disparities in diabetes rates? Thriftiness of Insulin Storage of fat Storage of glucose in liver Insulin resistance means higher insulin levels Insulin resistance means less growth and less fuel for muscles 8

9 Overnutrition In adults obesity causes diabetes Gene- environment mismatch What about in infants? ú birth weight was studied and an association with CVD was found. 9

10 Thrifty Phenotype Reported that developmental factors play a role Individuals with the same genes can end up following one of two pathways: ú No intrauterine stress plentiful nutrition no insulin resistance ú Stress, inadequate nutrition insulin resistance 10

11 Developmental Origins of Adult Disease Risk of coronary disease correlates with BMI in adults Barker et al found opposite relationship in infants Diabetes has the same pattern more in fatter adults, less in fatter infants Fetal Undernutrition - Small Babies IUGR babies reduced growth rate Stress induces other changes ú Lipid profile ú Glucose metabolism ú Blood pressure ú Visceral fat storage 11

12 Small for Gestational Age Preferentially deposit fat in visceral depot Short term energy balance Innervated by sympathetic nervous system Increased ability to respond to stress and to mobilize resources Visceral fat Free fatty acids Human babies have big brains Unlike muscles, the brain has fixed metabolic needs In nutritional stress, the brain needs fuel 12

13 Visceral fat and Insulin resistance IR makes growth slow and increases glucose available for the brain Visceral fat mobilization causes FFA release So in stressed and underfed infants/children the brain gets the fuel that it needs. Fetus senses environment Nutritional stress in utero Anticipates future environment Nutrient poor environment - no diabetes, no cardiovascular disease 13

14 Big brains are human specific How can we test the hypothesis that insulin resistance and visceral fat metabolism are adaptations that protect the brain? Tradeoffs Energy is finite Physiology and metabolism trade- offs What is the major source of mortality for small babies/toddlers? 14

15 Undernourished children die from infections Most childhood deaths are from infectious diarrhea Peak in early infancy and at age 2 In traditional societies, age 2 is time of weaning breast milk cannot keep up with demand. Undernourished children are at high risk of death at this time. American Journal of Clinical Nutrition, Vol. 80, No. 1, , July 2004 IR blocks muscle glucose uptake Increases blood glucose Increases glucose availability for non- insulin dependent tissues: immune system, brain placenta and mammary gland.* This contributes to defense against pathogens Fernandez-Rael. Genetic Predispositions to Low Grade Inflammation in Type II Diabetes. Diabetes Technology and Therapeutics (1):

16 Resource Allocation Immune cells ú In times of stress and infection, metabolic requirements of white blood cells skyrockets ú Do not require insulin dependent glucose shunt Insulin resistance has the effect of delivering more fuel to the immune system Perhaps insulin resistance is promotes survival of undernourished children from diarrhea. Short term vs Long term effects Short term mild insulin resistance may help body fend off infection Long term becomes full blown diabetes What evolutionary medicine concept is this? 16

17 Summary Evolutionary paradox of obesity/diabetes Thrifty gene hypothesis Thrifty phenotype hypothesis Effects of small for gestational age (SGA) Adaptive role of visceral fat in SGA infants Fixed demands of brain development Role of infection 17